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Show Journal of Clinical Neuro-ophthalmology 13(4): 275-280, 1993. Digoxin Toxicity Recognizing the Varied Visual Presentations lady R. Piltz, M.D., Christian Wertenbaker, M.D., Scot E. Lance, M.D., Thomas Slamovits, M.D., and Harold F. Leeper, M.D., ph.D. © 1993 Raven Press, Ltd., New York We report three cases of digoxin toxicity presenting with decreased visual acuity, unaccompanied by the classic visual symptom of xanthopsia. Visual function improved and symptoms diminished upon lowering of blood digoxin level. Electroretinographic (ERG) abnormalities in the first case were suggestive of a cone deficit, which supports recent electrodiagnostic and labeled tracer studies implicating retinal dysfunction in the pathogenesis of digoxin toxicity. The second patient presented with visual symptoms exclusively. Evaluation of the third case was hampered by advanced retinitis pigmentosa and the presentation was complicated by a syncopal episode. Digoxin toxicity is a potentially lifethreatening condition. Ophthalmologists and neurologists may be the first physicians consulted. It must be considered in the differential diagnosis in patients with otherwise unexplained visual loss. Key Words: Cardiac glycosides-Digitalis-DigoxinDyschromatopsia- Ocular toxicity-Systemic toxicityVisual loss-Xanthopsia. From the Scheie Eye Institute (J.R.P.), Department of Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Departments of Ophthalmology (C.S., T.S.), Neurology (C.W., T.S.), and Neurosurgery (T.S.), Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York; Department of Ophthalmology, University of South Florida, (S.E.L.), Sarasota, Florida; Department of Ophthalmology (H.F.L.), Wheeling Eye Institute, Wheeling, West Virginia, U.S.A. Address correspondence and reprint requests to Dr. ]ody R. Piltz, Scheie Eye Institute, 51 North 39th Street, Philadelphia, PA 19104, U.S.A. 275 Acute or subacute visual loss unexplained by objective ophthalmoscopic findings frequently leads to extensive neuro-ophthalmic evaluation. Toxicity to digoxin and other cardiac glycosides is often overlooked in the differential diagnosis of visual loss (1-4). Physicians are more likely to consider a diagnosis of digoxin toxicity if a history of xanthopsia is elicited, this being the symptom best known to physicians. Xanthopsia, however, is frequently absent even in severe toxicity to digoxin (1,2,5,6). Digoxin is a widely prescribed drug with a low margin of safety. Therapeutic and toxic serum levels overlap. It is estimated that up to 20% of patients taking digoxin exhibit some degree of toxicity, and up to 95% of toxic patients have visual symptoms. Visual symptoms can occur with serum levels within the therapeutic range (7,8). One would expect that visual complaints related to digoxin toxicity should be widespread; however, digoxin toxicity is rarely diagnosed in clinical practice on the basis of visual disturbances. Since the disorder is potentially life-threatening, it is imperative that all physicians be able to recognize digoxin toxicity, even in its subtler forms and in the absence of xanthopsia. We report three patients who had decreased visual acuity without xanthopsia as the presenting feature of digoxin toxicity. CASE 1 An 88-year-old white woman complained of progressive, generalized "dimming" of vision in both eyes over the previous week; she also had developed nausea, vomiting, diarrhea, and malaise. Two months earlier on a routine eye examination her best corrected visual acuity was 20/40 - in both 276 J. R. PILTZ ET AL. eyes. She was bilaterally aphakic and had agerelated macular degeneration. Her medical history was significant for hypertension and congestive heart failure. Her medications were Lanoxin 0.25 mg q.d., Vasotec 5 mg q.d., Persantine 50 mg q.d., hydrochlorothiazide 50 mg q.d., and aspirin 325 mgq.d. On admission, her best corrected visual acuity was 20/400 in both eyes. She identified lout of 12 Ishihara pseudoisochromatic color plates with each eye. Pupillary responses and ocular motility were normal; biomicroscopic and funduscopic findings were unchanged from baseline. She was unable to adequately respond on Goldmann perimetry. Computerized tomography of the brain and orbits without contrast was normal. A Westegren sedimentation rate was 78 mm/h. The patient was started on oral prednisone; this was discontinued 3 days later when bilateral temporal artery biopsies were found to be negative. The patient's digoxin level obtained on admission was 6.1 nglml (therapeutic range: 0.8--2.0 ngl ml). Because of the probable diagnosis of digoxin toxicity, she was questioned again about visual symptoms but denied dyschromatopsia, scotomata, or photopsias. Digoxin was discontinued, and the drug level returned to normal after 72 hours. An electroretinogram (ERG) was obtained 1 week after presentation. The amplitude of the dark adapted, flash ERG was decreased to approximately 20% of normal for the right eye and 45% of normal for the left eye. The implicit time of the b-wave was increased in both eyes. Photopic ERG responses were not clinically recordable (Fig. 1). The patient's visual acuity gradually improved. Three months after presentation, her best corrected visual acuity was 20/60 in each eye and 201 40-2 binocularly; the remainder of the examination was unchanged. Repeat flash ERG recordings demonstrated slightly improved scotopic amplitudes (approximately 30% and 60% of normal in the right and left eyes, respectively) and normal-ization of the b-wave implicit time for both eyes. Photopic responses demonstrated normal b-wave implicit time and amplitudes of 40% and 45% of normal for the right and left eyes, respectively (Fig. 2). CASE 2 A 78-year-old woman presented with a 2-week history of decreased visual acuity bilaterally. She described a perception of brightness and whiteness which appeared as "snow" throughout her vision. The whiteness obscured her perception of colors. She denied xanthopsia or nausea and had no other systemic symptoms. Her past ocular history was unremarkable. Visual acuity 2 years before was 20/20 bilaterally. Two months prior to presentation, she underwent an aortic valve replacement and was started on Lanoxin 0.25 mg daily. Her past medical history was also positive for hypertension and angina. Additional medications included furosemide, ferrous sulfate, aspirin, and potassium supplementation. Coumadin was discontinued within 1 month after surgery. On examination, best corrected visual acuity was 20/50 00 and 20/70 - as. She correctly identified only the test plate of the Ishihara pseudoisochromatic color plates with each eye. Pupillary examination and ocular motility were normal. Early nuclear sclerotic cataracts and mild pigmentary changes of the macula were noted bilaterally. Goldmann visual fields revealed generalized depression of the field and a 10-degree relative central scotoma to the I3E isopter as. The digoxin level at the time of presentation was 2.2 nglml (therapeutic range: 0.5-2.0 ng/ml). Digoxin was discontinued for 3 days and then restarted at 0.125 mg daily. She noted improvement of her acuity and color vision within 10 days. One month after presentation, visual acuity was 201 25 - bilaterally. She correctly read 12 of 15 Ishihara color plates with each eye. Goldmann visual fields FIG. 1. Case 1: Electroretinogram performed 1 week after admission. A: Scotopic flash electroretinogram. 8: Photopic electroretinogram. A JClin Neuro-ophthalmol, Vol. 13, No.4, 1993 B JJ.J .LLJ J....l.u.1 DIGOXIN TOXICITY: VISUAL PRESENTATIONS 277 A 'w... _ /~ I .. I \ .. ...'~t.#ItttI.".".. ""I.'" \..,-. /II~'.j \,,\ I, 1. \~"·,f~,..J \ •. It ••f. jV" \""' \:\'. ) • •.....IfIIIII... ., t .\ f· ...-. I ".,- \ f \'.../ B ;'" \.:'....:.\/-.,. ,~••'=-\ ,.f..,,;'/. ',} .uJ...U ..LLJ..1.U FIG. 2. Case 1: Electroretinogram performed 3 months after admission. A: Scotopic flash electroretinogram. B: Photopic electroretinogram. revealed resolution of the abnormalities au. Repeat digoxin level was 0.7 ng/mI. CASE 3 A 58-year-old woman with retinitis pigmentosa, high myopia, and rheumatic heart disease was functioning visually at her usual level (able to play cards and read for short periods) until 5 days prior to admission when she had a syncopal episode, after which she noted darkening of her vision. On ophthalmic examination 1 year earlier, her visual acuity was 20/50 in the right eye and hand motions in the left eye. The right eye was aphakic and the left eye had a dense posterior subcapsular cataract and a macular staphyloma. Both fundi exhibited bone spicule pigmentary changes compatible with advanced retinitis pigmentosa. Past medical history was significant for mitral valve stenosis with congestive heart failure secondary to rheumatic heart disease. She had undergone mitral valve commisurotomies in 1959 and 1979. She had suffered an embolic cerebrovascular accident in 1976 and had episodes of atrial fibrillation requiring cardioversion in 1983. Her current medications were Lanoxin, 0.25 mg and 0.375 mg on alternate days, Lasix 80 mg q.d., Inderal 40 mg q.d., Coumadin, stopped by the patient 4 days prior to admission, Norpace 100 mg q.i.d., and potassium supplements. On admission, the patient described extreme darkness of vision, headache, lethargy, and dizziness. Visual acuity was 20/200 in the right eye and light perception in the left eye. The remainder of the ophthalmic examination was unchanged. On confrontation visual field testing, the patient could see hand motions centrally and in the far temporal and nasal periphery of the right eye; formal perimetry was not performed. Computed tomography revealed multiple lacunes without acute hemor-rhage or infarction. Intravenous anticoagulation was instituted. The digoxin level obtained on admission was 4.5 ng/mI. Further questioning revealed that the patient had also had nausea and vomiting prior to admission. Digoxin was withheld for 2 days. On days, 1,2 and 3 after admission, the levels decreased to 3.4, 2.7, and 1.2 ng/ml, respectively. By the third day, the patient noted marked improvement of acuity and brightness of vision. Her color perception subjectively returned to baseline, and she felt she had returned to normal systemically. Visual acuity was 20/70 in the right eye and hand motions in the left eye. DISCUSSION The visual symptoms secondary to toxicity of digoxin and other cardiac glycosides are well described in the medical and ophthalmic literature, and are known to occur even with therapeutic serum levels (7,8) (Table 1). However, this diagnosis is infrequently entertained by clinicians when evaluating patients with visual loss. William Witherington (9) described many of the toxic effects of the cardiac glycosides in his classic treatise on the foxglove in 1785. "The foxglove when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; ... syncope, death." TABLE 1. Ophthalmic symptoms of digoxin toxicity Blurred vision, trouble reading Dim, hazy, misty, snowy vision Xanthopsia and other dyschromatopsias Flashing, scintillating lights Moving spots and shapes Diplopia Pain with ocular movements / Clin NeuTo-ophthalmol, Vol. 13. No.4. 1993 278 J. R. PILTZ ET AL. Since 1925, numerous studies have described the visual symptoms and attempted to identify the site of visual toxicity in digitalis intoxication. While xanthopsia is known as the classic symptom of digoxin toxicity (1,2,9), the most common symptom is blurred vision with or without dyschromatopsia (2,6,10). In one series of 179 patients, 95% had visual complaints, most commonly difficulty reading and hazy vision (4). Vision is often worse in bright light (11). Patients frequently describe that everything appears covered by snow, frost, or mist (2,12,13). Visual impairment can be severe and cases of total blindness have been reported (14). Flashing and scintillating lights, moving spots and moving shapes of various colors have also been described (3,12,13,15,16). Bilateral central, paracentral and centrocecal scotomas have been demonstrated, most commonly with the tangent screen and a 1/1000 or 211000 white target (2,3,10,17-21) (Table 2). Dyschromatopsias may also occur in digoxin intoxication. These most often consist of everything appearing washed in yellow (xanthopsia); however, green and yellow-red vision has also been described (2,5,22-24). In this type of dyschromatopsia, a color is superimposed on the visual world as if everything were covered by a color wash or seen through a colored filter (25). This "color wash" dyschromatopsia, also known as "chromatopsia" (26), has a relatively limited differential diagnosis (26-34) (Table 3) and is different from the deficit that occurs with optic neuropathies, in which colors appear desaturated. One of us (C.W.), however, has seen a patient who complained of xanthopsia in the recovery phase of optic neuritis. Reitbrock and AIken (35) found that 80% of digoxin-intoxicated patients (digoxin level >2.5 ng/ml) had color vision abnormalities on the Farnsworth- Munsell 100 Hue test (FM 100). Both redgreen and blue-yellow deficits have been found (4,7,8,23,24,36). Color abnormalities have also been identified at therapeutic dosages; 20% of patients with serum levels less than 1.5 ng/ml and 50% of patients with levels between 1.5 and 2.5 ng/ml had significant color deficits (7). Investiga- TABLE 2. Ophthalmic signs of digoxin toxicity Decreased acuity Central scotomas Color vision defects Abnormal dark adaptation Abnormal electroretinogram Mydriasis Ocularmotor palsies JGin Neuro-ophthalmol, Vol. 13, No.4, 1993 TABLE 3. Differential diagnosis of "color wash" dyschromatopsia Digoxin toxicity and toxicity of other cardiac glycosides Other drugs, including barbiturates, cannabis, thiazide diuretics, methanol, phenacentin, streptomycin, sulfathiazole, trimethadione (27, 28) Occipital lesions (28, 29) Aftereffects, such as from computer video display (McCullough aftereffect (30, 31)) and snow-induced erythropsia (32) Intraocular hemorrhage (33) Postcataract surgery dyschromatopsia (34) tors are exploring the use of color vision testing in the diagnosis of digoxin intoxication (37-40). Mydriasis and diplopia have occasionally been associated with digoxin toxicity (1,2,10,16,18). A recent report describes pain with eye movements related to digoxin administration (41). Acute toxicity may be precipitated by many factors. Elevated serum levels can result from an increase in dosage, a change to a preparation with greater bioavailability, or decreased elimination secondary to renal dysfunction. Electrolyte disturbances such as hypokalemia and hypercalcemia as well as concurrent administration of other drugs (diuretics, corticosteroids, quinidine) may result in toxicity (42). Visual symptoms may occur days to years after starting the drug. Visual changes may precede systemic symptoms (5). In the vast majority of cases, toxic visual effects are reversible with improvement of acuity and color vision within days to months. In a few cases reported, central scotomas persisted throughout the follow-up period so the full reversibility of these deficits is uncertain (21). The site of toxicity responsible for the visual symptoms has been debated for decades. Langdon and Mulberger (22) and Carroll (5) felt that the visual symptoms originated in the visual cortex. Weiss (43) felt that xanthopsia was due to brainstem dysfunction. Demonstration of cellular alterations in the cerebral cortex and spinal cord of cats after administration of toxic doses of digitalis supported the central dysfunction theory (44). For many years most investigators thought that the most likely site of damage in digitalis intoxication was the optic nerve (2,10,17-21,45,46). More recent investigations, however, have identified significant retinal dysfunction in digitalis toxicity and have shed some doubt on the older hypotheses (11,23,47,48). In 1962, Denden (17) measured the flicker ERG in a patient with digitalis toxicity and noted disturbed responses to the longer wavelengths of light. In 1965, Gibson and colleagues (23) found an abnormal cone ERG and dark- DIGOXIN TOXICITY: VISUAL PRESENTATIONS 279 adaptation profiles in a patient with digitalis toxicity. Robertson and colleagues (48) in 1966 showed elevated dark-adaptation thresholds, particularly in the cone region, in two of three normal subjects given nontoxic doses of digitalis. Weleber and Shults (11) noted abnormalities of the ERG and color vision, consistent with cone dysfunction, in a 70-year-old man with digoxin toxicity exacerbated by concomitant administration of quinidine. These investigations based on ERG and darkadaptation studies suggest that retinal pathology, particularly affecting the cones, is responsible for the visual abnormalities of digitalis toxicity (11,23, 47A8). Additional support for a retinal site of toxicity has been provided by tracer studies which have shown much higher accumulations of digoxin in the retina than in other tissues, including the optic nerve and brain (49-51). Digoxin toxicity might involve inhibition of sodium-potassium-activated adenosine triphosphatase, which has been identified in high concentration in the outer segments of the rods; inhibition of the enzyme could impair photoreceptor repolarization (11,50,52) Lissner and colleagues (50), however, found the greatest uptake of digoxin in the inner retinal layers, particularly in the ganglion cell layer, with little uptake in the photoreceptors. To date, the precise site of toxicity has not been identified. Our cases presented with significant deficits of visual function, predominantly dimming of vision and decreased acuity. None of our patients complained of xanthopsia. The first case was confounded by an elevated erythrocyte sedimentation rate, leading to evaluation of temporal arteritis. The second patient had no systemic symptoms of digoxin toxicity and presented solely because of visual dysfunction. Even though the digoxin level was only minimally elevated, the visual symptoms were marked. Both acuity and color vision were disturbed, however, xanthopsia was not present. The presentation of the third patient was misleading because her visual symptoms were directly preceded by a syncopal episode. Given her previous rheumatic heart disease and atrial fibrillation, an embolic event as a cause of her symptoms was entertained. In retrospect, however, digoxin toxicity may have precipitated an arrhythmia leading to the syncope. While bilateral loss of vision can result from occipital ischemia, the time course of her recovery strongly suggests that retinal toxicity from digoxin was the cause of her disorder. While cardiac, gastrointestinal, and neuromuscular symptoms are commonly encountered in digoxin toxicity (Table 4), visual dysfunction is fre- TABLE 4. Systemic signs and symptoms of digoxin toxicity Cardiac Atrial and ventricular arrhythmias Atrioventricular block Sinus arrhythmia, sinus arrest Characteristic changes of the electrocardiogram Gastrointestinal Anorexia, nausea, vomiting, diarrhea, abdominal pain Neurologic Headache, fatigue, malaise Neuralgic pain Disorientation, confusion, delirium Convulsions Other Skin rashes Eosinophilia Gynecomastia quently the reason for presentation to the doctor. The ophthalmologist or neurologist may therefore be the first physician consulted by a patient with digitalis toxicity (6). Accompanying systemic symptoms may not be volunteered by the patient and may go unrecognized if not specifically elicited by the ophthalmologist. The most common visual complaint is difficulty reading and hazy vision, often described as images covered by frost or mist, followed by dyschromatopsia and photopsias (4). 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